Stem Cell Clinic

MD Anderson researchers present cellular therapy advances at the 2022 ASCO Annual Meeting – EurekAlert

Highlights include three-year data from ZUMA-2, gamma delta CAR T cell therapy and NK cell combination treatment

University of Texas M. D. Anderson Cancer Center

ABSTRACTS 7518, 7509, 8009

Promising clinical results with cellular therapies for patients with blood cancers highlight advances being presented by researchers from The University of Texas MD Anderson Cancer Center at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

These findings include long-term outcomes of patients receiving an infusion of brexucabtagene autoleucel (KTE-X19) for mantle cell lymphoma, efficacy of gamma delta CAR T therapy for aggressive B-cell lymphoma and responses of umbilical cord blood-derived expanded natural killer cells when given together with combination therapy before stem cell transplant.

CAR T cell therapy shows durable responses after three years for patients with mantle cell lymphoma (Abstract 7518) Three-year follow-up data from the Phase II ZUMA-2 trial showed a long-term survival benefit and low disease relapse potential with one infusion of the anti-CD19 chimeric antigen receptor (CAR) T cell therapy brexucabtagene autoleucel (KTE-X19) in patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL). Principal investigator Michael Wang, M.D., professor of Lymphoma and Myeloma, presented results from the trial, and study results were published in the Journal of Clinical Oncology.

The updated results include all 68 patients treated with KTE-X19 on the trial with an additional two years of follow-up. After 35.6 months median follow-up, the overall response rate was 91%, with a 68% complete response rate. The median duration of response was 28.2 months, with 25 of 68 treated patients still in ongoing response at data cutoff.

This represents the longest follow-up of CAR T cell therapy in patients with mantle cell lymphoma to date, Wang said. It is encouraging to see this therapy induced durable long-term responses and a low relapse rate for these patients.

All patients had R/R disease after receiving up to five therapies, and all had received previous Brutons tyrosine kinase (BTK) inhibitor therapy. BTK inhibitors have greatly improved outcomes in R/R MCL, yet patients who have subsequent disease progression are likely to have poor outcomes, with median overall survival of just six to 10 months. Few patients in this category qualify to proceed to an allogeneic stem cell transplant.

Response and survival benefits were positive regardless of the prior BTK inhibitor type. Ongoing effectiveness trended lower in patients with prior acalabrutinib exposure. More investigation is needed to determine the mechanism behind these differences. The findings support future study of CD19-directed CAR T cell therapy in patients with high-risk MCL in earlier treatment lines.

The researchers also evaluated minimal residual disease (MRD) as an exploratory endpoint using next-generation sequencing on 29 patients. Of those, 24 were MRD-negative at one month, and 15 of 19 with available data were MRD-negative at six months. Circulating tumor DNA analysis of MRD at three and six months was predictive of disease relapse.

The treatment was well tolerated, as reported in previous studies with this therapy. Only 3% of treatment-emergent adverse events (AE) of interest occurred since the primary report. The most frequent Grade 3 AE was neutropenia.

The study was funded by Kite Pharma, a Gilead Company. Wang has received research support and has served on the advisory board and as a consultant for Kite Pharma. A complete list of collaborating authors can be found within the abstract here.

Allogeneic gamma delta CAR T cell therapy displayed encouraging efficacy in B-cell lymphoma (Abstract 7509) In the Phase 1 GLEAN trial of ADI-001, an anti-CD20 CAR-engineered allogeneic gamma delta T cell product, the treatment was well tolerated and showed continued efficacy in patients with R/R aggressive B-cell lymphoma. Results from the ongoing trial were presented by Sattva Neelapu, M.D., professor ofLymphoma and Myeloma.

The first-in-human trial enrolled ten patients and eight were evaluable and monitored for at least 28 days. The median age was 62 years and patients received a median of 4 prior therapies. At Day 28, the overall response rate (ORR) and complete response (CR) rate based upon PET/CT was 75%. The ORR and CR rate was 80% at dose levels two and three combined. The ORR and CR rate in CAR-T relapsed patients was 100%.

The responses to ADI-001 in this population of heavily pre-treated and refractory lymphoma patients, including in those with prior CD19 CAR T cell therapy, is very promising, Neelapu said. These results suggest the potential for off-the-shelf gamma delta CAR T cell therapy to be an effective treatment possibility for patients with B-cell lymphoma.

While autologous CD19-targeted CAR T cell therapy has been effective in R/R large B-cell lymphoma, there remains a need for alternative cell-based therapies. This study uses a subset of T cells, known as gamma delta 1 T cells, isolated from the peripheral blood of donors as the basis for CAR T cell therapy.

Gamma delta 1 T cells are desirable because they are able to combine both innate and adaptive mechanisms to recognize and kill malignant cells, and high levels of these cells in hematologic and solid tumors are associated with improved clinical outcomes. ADI-001 expresses major histocompatibility complex (MHC)-independent gamma delta T cell receptors, therefore lowering the risk of graft versus host disease (GvHD) without the need for gene editing.

The median age on the study was 62 years, and patients had received a median of 4 prior therapies. The treatment was well tolerated with most related events being grade 1 or 2. There were two cases of cytokine release syndrome and one case of immune effector cell-associated neurotoxicity syndrome. There were no reported cases of GvHD or dose-limiting toxicity.

Enrollment in the trial is ongoing and a potentially pivotal program is planned.

The study was funded by Adicet Bio, Inc. Neelapu has received research support and has served on the advisory board and as a consultant for Adicet Bio and has intellectual property related to cell therapy. A complete list of collaborating authors can be found within the abstract here.

Expanded NK cells combined with chemoimmunotherapy achieved durable responses in multiple myeloma (Abstract 8009) Results from the expansion phase of a Phase II clinical trial demonstrated that umbilical cord blood-derived expanded natural killer (NK) cells combined with chemotherapy and immunotherapies achieved durable responses in patients with multiple myeloma. Results from the completed clinical trial were presented by Samer Srour M.D., assistant professor of Stem Cell Transplantation & Cellular Therapy.

Thirty patients on the trial received NK cells plus elotuzumab (an immunotherapy monoclonal antibody), lenalidomide (an immunomodulatory drug) and high-dose melphalan chemotherapy before autologous stem cell transplant (ASCT).

At three months post-transplant, 97% of patients achieved at least a very good partial response (VGPR), including 76% with a complete response or stringent complete response, while 75% were minimal residual disease (MRD)-negative. At a median follow-up of 26 months, only four patients had progressed. At two years, the progression-free survival rate was 83% and the overall survival rate was 97%.

Patients with high-risk multiple myeloma have more options to treat their disease than previous years, but they continue to have poor outcomes, Srour said. These results indicate excellent hematologic and minimal residual disease responses and improved survival for these patients, suggesting this approach could provide an additional treatment opportunity.

NK cells are white blood cells that monitor the body for virus-infected and cancerous cells. MD Anderson researchers pioneered the approach to isolate and expand NK cells from umbilical cord blood to be used as cellular therapies. Lenalidomide enhances NK cell function and antibody-mediated cell toxicity against tumor targets. Preclinical data showed that lab-expanded NK cells demonstrated higher elotuzumab-mediated cytotoxicity against myeloma targets than non-expanded cells, and that the addition of elotuzumab to lenalidomide amplified the cord blood-NK cell antibody-dependent cellular cytotoxicity against a commonly used cell line to evaluate novel therapies for multiple myeloma (MM1.S) targets.

The study enrolled 30 patients with high-risk multiple myeloma, with a median age of 63. Twenty-nine patients (97%) had Revised Multiple Myeloma International Staging System (R-ISS) stages 2/3, 40% had 2 high-risk genetic abnormalities, and 23% had deletions or mutations of TP53. The primary endpoints were best response rate (VGPR) and MRD three months after ASCT.

Before the ASCT, stem cells are taken from the patient and stored. After treatment with the immunotherapy and chemotherapy drugs, stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

The treatment was well tolerated, with no unexpected serious adverse effects attributable to NK cells noted. The investigators plan to launch a randomized clinical trial to further explore this treatment combination for patients with high-risk multiple myeloma.

This study was supported with funding from the High-Risk Multiple Myeloma Moon Shot, part of MD Andersons Moon Shots Program, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients lives. The research also was supported by Celgene, a Bristol Myers Squibb company.

Srour has no conflicts of interest. A complete list of collaborating authors can be found within the abstract here.

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MD Anderson researchers present cellular therapy advances at the 2022 ASCO Annual Meeting - EurekAlert

Asymmetrex Presents New Developments in its Rapid Stem Cell Counting Technology at the ARMI|BioFabUSA Meeting in the Millyard on Regenerative Medicine…

Asymmetrex reports algorithms for rapid quantification of therapeutic stem cells

BOSTON (PRWEB) June 09, 2022

In 2021, stem cell biotechnology company Asymmetrex announced its award of a Technical Project grant from ARMI|BioFabUSA. ARMI assembles, integrates, and leads academic, government, and industry partners in coordinated research and development with a unique vision of accelerating innovation in the biomanufacturing of products and treatments for regenerative medicine. Asymmetric became a member company of ARMI|BioFabUSA less than a year before being selected to evaluate whether its unique tissue stem cell counting technology could be successfully adapted for use in cell and tissue biomanufacturing.

Now, a little over a year later, the company is reporting the results of its evaluation in two presentations in ARMI|BioFabUSAs Spring Meeting in the Millyard R&D summit, scheduled for September 7-9. On the opening morning of the summit on September 7, Asymmetrex presented an interactive Technology Demonstration of the capabilities of the newly automated software for its kinetic stem cell (KSC) counting technology. Automation is one of the four main ARMI|BioFabUSA principles for accelerating biomanufacturing capability. The others are modularity, scalability, and closed operability.

The new software automation provides a tenfold increase in the speed of determinations of changes in the relative fractions for tissue stem cells and their related cell subpopulations during biomanufacturing. No other technology has this capability; and the new software automation allows it to be performed with greater speed and even greater precision.

Asymmetrexs second presentation was a poster displayed at the summits poster session on the evening of September 8. The poster provides a first look at the industry potential of validated rapid-counting algorithms for therapeutic stem cells. The speed and precision achieved by the software automation makes the derivation of these unique biological equations routine. Called Rabbit algorithms for their speed, Asymmetrex is currently developing online calculators for access to their use. The calculators use simple conventional cell count data to determine the specific fraction or dose of the tissue stem cells present in a biomanufacturing or treatment sample.

The facility and speed of the rapid stem cell counting algorithms enable straightforward integration of KSC counting for monitoring therapeutic stem cells in cell and tissue biomanufacturing processes. Asymmetrex is now designing a pilot online rapid-counting beta-test with ARMI|BioFabUSA bioengineers who collaborated in the research. Asymmetrex founder, James L. Sherley, M.D., Ph.D., expresses the companys excitement with the new advances, Determining the dose of therapeutic stem cells is now more than just possible for the first time. With ARMIs support it's getting easy to do, too!

About Asymmetrex

Asymmetrex, LLC is a Massachusetts life sciences company with a focus on developing technologies to advance stem cell medicine. The companys U.S. and U.K. patent portfolio contains biotechnologies that solve the two main technical problems stem cell-specific quantification and stem cell expansion that have stood in the way of more-effective use of human adult tissue stem cells for regenerative medicine and drug development. Asymmetrex markets kinetic stem cell (KSC) counting, the first technology for determination of the dose and quality of tissue stem cell preparations for use in stem cell transplantation medicine and pre-clinical drug evaluations. Asymmetrex is a member company of the Advanced Regenerative Manufacturing Institute | BioFabUSA (ARMI) and the Massachusetts Biotechnology Council (MassBio).

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Depth of Response and Treatment Duration in Newly Diagnosed MM – Cancer Network

Rafael Fonseca, MD: While we have criteria that allows us to categorize the depth of the response for myeloma patients, we are learning that criteria perhaps in time will become more of an academic exercise. We want patients who are going to go through transplant - and that is before transplant and certainly after transplant - to achieve very deep responses and in the post-transplant period to achieve MRD negativity. So, we all see patients that are referred to the transplant centers who may have initiated on a regimen. Perhaps sometimes even a 3-drug regimen that may have, what I would say, is of optimal response. They're going into transplant with a partial response.

Well, 10 years ago, it was perfectly fine to move forward. I would suggest that those patients need to derive better disease control from an alternative combination before they proceed to transplant. For two reasons, the depth of the response seems to correlate with long-term outcomes but also there's a potential and some of you might point out this hypothetical. But there is a potential for contamination of the product or residual cells post stem cell transplant. So, I think we want to have patients go into transplant and certainly come out of transplant with the best response as possible.

In our clinical practice for patients who will go through the stem cell transplant, we do a very thorough assessment, post-stem cell transplant to determine what the next steps would be. And sometimes we have offered consolidation for patients who are still MRD positive post-stem cell transplant with an understanding that those pathways may vary according to the genetic subtype of the disease. But certainly, there's good evidence that for patients with high-risk disease leaving cells behind is associated with a very high risk of early relapse. Now whether one does that or not, the next step is of course maintenance and maintenance is supported by several randomized trials as well as a meta-analysis that shows that as of now maintenance with Lenalidomide is the standard of care. There are other studies that are exploring different maintenance strategies the use of Carfilzomib, for instance the FORTE [trial], the use of daratumumab as is being explored in the AURIGAclinical trial.

The reality is that most patients benefit from what we know today for longer duration of therapy. Our patients are going to maintenance do so with the understanding that as long as they tolerate the treatment and they have access to the treatment and assuming it's working, that is we're not seeing evidence of a disease recurrence, we will keep those patients going on that maintenance treatment. Now the reality is that the real-world evidence available from the United States suggests that most patients don't go beyond 2 years. The reasons for this are multiple but certainly a component of that is toxicity so patients having fatigue, having chronic diarrhea. I would say to patients yes, we're going to start maintenance that rather go for a longer period of time, but I understand that many patients have to stop treatment because of the symptomatology that will interfere with their quality of life.

Now we're all hoping for a future, and hopefully not too distant future, where the availability of information regarding MRD information would allow us to confidently and without other considerations stop therapy. So now we stop therapy for multiple reasons. I bring the MRD information into the bedside as we make those decisions, but there might be a more clear future where MRD itself dictates who can continue in therapy and who can stop.

A legitimate question is what will happen in the future regarding stem cell transplant for those patients that are eligible and there are many possibilities. One of them is that transplant will remain as an important step in consolidating that initial gain of induction therapy and that perhaps will build on that. We will address residual disease through novel strategies. It could include molecularly targeted strategies like Venetoclax for t(11;14) patients or immunology strategies such as could be bispecific antibodies or CAR T-cells.

There are other possibilities as well and one of the tantalizing one is that transplant might not be needed and while transplant has been very effective, it does carry a burden of symptoms. And the time away from work, from family, the hair loss, all those things. So perhaps, we will see induction therapy in other ways followed by either a CAR T-cell or one of the bispecifics, and why not? Perhaps even think of a chemotherapy free regimen that could be a bispecific plus a targeted agent that results in very significant cytoreduction and avoids the need of oculating [ph] agents. But again, this is all in in flux, evolving and being addressed through multiple clinical trials.

Transcript edited for clarity.

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Depth of Response and Treatment Duration in Newly Diagnosed MM - Cancer Network

UB-led study presents critical step forward in understanding Parkinson’s disease and how to treat it – University at Buffalo

BUFFALO, N.Y. A new study led by a researcher in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo has important implications for developing future treatments for Parkinsons disease (PD), a progressive nervous system disorder that affects movement and often includes tremors.

In this study, we find a method to differentiate human induced pluripotent stem cells (iPSCs) to A9 dopamine neurons (A9 DA), which are lost in Parkinsons disease, says Jian Feng, PhD, professor of physiology and biophysics in the Jacobs School and the senior author on the paper published May 24 in Molecular Psychiatry.

These neurons are pacemakers that continuously fire action potentials regardless of excitatory inputs from other neurons, he adds. Their pacemaking property is very important to their function and underlies their vulnerability in Parkinsons disease.

This exciting breakthrough is a critical step forward in efforts to better understand Parkinsons disease and how to treat it, says Allison Brashear, MD, UBs vice president for health sciences and dean of the Jacobs School. Jian Feng and his team are to be commended for their innovation and resolve.

Feng explains there are many different types of dopamine neurons in the human brain, and each type is responsible for different brain functions.

Nigral dopamine neurons, also known as the A9 DA neurons, are responsible for controlling voluntary movements. The loss of these neurons causes the movement symptoms of Parkinsons disease, he says.

Scientists have been trying hard to generate these neurons from human pluripotent stem cells to study Parkinsons disease and develop better therapies, Feng says. We have succeeded in making A9 dopamine neurons from human induced pluripotent stem cells. It means that we can now generate these neurons from any PD patients to study their disease.

Feng notes that A9 DA neurons are probably the largest cells in the human body. Their volume is about four times the volume of a mature human egg.

Over 99 percent of the volume is contributed by their extremely extensive axon branches. The total length of axon branches of a single A9 DA neuron is about 4.5 meters, he says. The cell is like the water supply system in a city, with a relatively small plant and hundreds of miles of water pipes going to each building.

In addition to their unique morphology, the A9 DA neurons are pacemakers they fire action potentials continuously regardless of synaptic input.

They depend on Ca2+ channels to maintain the pacemaking activities. Thus, the cells need to deal with a lot of stress from handling Ca2+ and dopamine, Feng says. These unique features of A9 DA neurons make them vulnerable. Lots of efforts are being directed at understanding these vulnerabilities, with the hope of finding a way to arrest or prevent their loss in Parkinsons disease.

Pacemaking is an important feature and vulnerability of A9 DA neurons. Now that we can generate A9 DA pacemakers from any patient, it is possible to use these neurons to screen for compounds that may protect their loss in PD, Feng notes. It is also possible to test whether these cells are a better candidate for transplantation therapy of PD.

To differentiate human iPSCs to A9 DA neurons, the researchers tried to mimic what happens in embryonic development, in which the cells secrete proteins called morphogens to signal to each other their correct position and destiny in the embryo.

Feng notes the A9 DA neurons are in the ventral part of the midbrain in development.

Thus, we differentiate the human iPSCs in three stages, each with different chemicals to mimic the developmental process, he says. The challenge is to identify the correct concentration, duration, and treatment window of each chemical.

The combination of this painstaking work, which is based on previous work by many others in the field, makes it possible for us to generate A9 DA neurons, Feng adds.

Feng points out there are a number of roadblocks to studying Parkinsons disease, but that significant progress is being made.

There is no objective diagnostic test of Parkinsons disease, and when PD is diagnosed by clinical symptoms, it is already too late. The loss of nigral DA neurons has already been going on for at least a decade, he says.

There was previously no way to make human dopamine neurons from a PD patient so we could study these neurons to find out what goes wrong.

Scientists have been using animal models and human cell lines to study Parkinsons disease, but these systems are inadequate in their ability to reflect the situation in human nigral DA neurons, Feng says.

Just within the past 15 years, PD research has been transformed by the ability to make patient-specific dopamine neurons that are increasingly similar to their counterparts in the brain of a PD patient.

Houbo Jiang, PhD, research scientist in the Department of Physiology and Biophysics, and Hong Li, PhD, a former postdoctoral associate in the Department of Physiology and Biophysics, are co first-authors on the paper.

Other co-authors on the study are: Hanqin Li, PhD, a graduate of the doctoral program in neuroscience and currently a postdoctoral fellow at University of California, Berkeley; Li Li, a trainee in UBs doctoral program in neuroscience; and Zhen Yan, PhD, SUNY Distinguished Professor of physiology and biophysics.

The study was funded by the Department of Veterans Affairs, National Institutes of Health and by New York State Stem Cell Science (NYSTEM).

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UB-led study presents critical step forward in understanding Parkinson's disease and how to treat it - University at Buffalo

Protein discovery reinvigorates promising new therapeutic – EurekAlert

image:A look at the structure of the SCF-based therapeutic. view more

Credit: The University of Texas at Austin / Cockrell School of Engineering

Several years ago, a promising therapeutic using stem cell factor (SCF) emerged that could potentially treat a variety of ailments, such as ischemia, heart attack, stroke and radiation exposure. However, during clinical trials, numerous patients suffered severe allergic reactions and development of SCF-based therapeutics stopped.

A research team led by engineers at The University of Texas at Austin has developed a related therapeutic that they say avoids these major allergic reactions while maintaining its therapeutic activity. The keys to the discovery, published recently inNature Communications, were the use of a similar, membrane-bound version of SCF delivered in engineered lipid nanocarriers.

"We envision this as something you can inject where you have lack of blood flow and it could induce blood vessels to grow in that area," said Aaron Baker, a professor in the Cockrell School of Engineering's Department of Biomedical Engineering, and one of the leaders on the project.

Stem cell factor is a cytokine, a type of soluble protein that can stimulate regeneration in the body and growth of stem cells. Its ability to help stem cells grow, especially in critical places like bone marrow, makes it very promising for many therapeutic applications. But when delivered to the body in clinical trials related to strokes, it caused mast cell growth, which activated the immune systems defenses and led to the allergic reactions.

The new therapeutic uses transmembrane stem cell factor, a version of the cytokine that tethered to a cell membrane. In the body, the transmembrane form can be cleaved off into to the soluble form, which travels around the body.

"We found this transmembrane stem cell factor has all the necessary therapeutic properties and without activating the immune system and causing allergic reaction," said Eri Takematsu, a former member of Bakers lab who is now a postdoctoral researcher at Stanford and was the first author on the paper.

The big problem with the transmembrane SCF is that, because its not soluble, it tends to just clump together in solution. So, the team developed lipid nanocarriers to help it say in solution and to tailor its activity towards different cell type. They looked specifically at using a liposomes (lipid bubbles) and lipid nanodiscs as carriers for transmembrane SCF.

"This type of nanodisc is something people haven't explored very much developing therapeutics before," Baker said. "It makes a little island of lipid around the transmembrane SCand holds it together with a ring of proteins, kind of like a lariat."

The researchers have patented their method, and the next step would be clinical trials. In order to do that, however, they need approval from the U.S. Food and Drug Administration to classify the therapeutic as aninvestigational new drug. In addition, they are continuing to fine-tune important details like correct dosage for patients.

Other team members on the project include Miles Massidda, Jeff Auster, Po-Chih Chen, ByungGee Im, Sanjana Srinath, Sophia Canga, Aditya Singh, Marjan Majid and Andrew Dunn from the Department of Biomedical Engineering; Michael Sherman from the Department of Biochemistry & Molecular Biology, University of Texas Medical Branch, Galveston; and Annette Graham and Patricia Martin of the Department of Biological and Biomedical Sciences at Glasgow Caledonian University in Scotland. The research was funded through grants from the American Heart Association, National Institutes of Health and the U.S. Department of Defense's Congressionally Directed Medical Research Programs.

Nature Communications

Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Senti Bio Debuts as Publicly Traded Company Focused on Developing Next-Generation Cell and Gene Therapies Engineered with Gene Circuits – BioSpace

- Business combination with Dynamics Special Purpose Corp. completed today; gross proceeds from transaction to Senti Bio expected to total approximately $156.5 million -

- Combined company Senti Bio will be listed on the Nasdaq Global Market under ticker symbol "SNTI" -

- IND filings for preclinical oncology candidates SENTI-202 and SENTI-301 anticipated in 2023 -

SOUTH SAN FRANCISCO, Calif., June 09, 2022 (GLOBE NEWSWIRE) -- Senti Biosciences, Inc. (Senti Bio), a biotechnology company developing next-generation cell and gene therapies using its proprietary gene circuit platform, today announced the completion of its business combination with Dynamics Special Purpose Corp. (DYNS; Nasdaq: DYNS), a special purpose acquisition company. Senti Biosciences, Inc., the resulting combined company, will commence trading on the Nasdaq Global Market under the symbol SNTI on June 9, 2022.

Over the last year, we have made significant pipeline progress in optimizing our gene circuit technology and generating promising data across our lead programs, SENTI-202 and SENTI-301, which we plan to advance toward IND filings in 2023, said Timothy Lu, MD, PhD, Chief Executive Officer and Co-Founder of Senti Bio. We believe that with the funding from this successful transaction, we are well positioned to maximize this unique opportunity to develop the next generation of gene circuit-enabled cell and gene therapies for patients in need.

Senti Bio is developing next-generation cell and gene therapies engineered with gene circuits, which are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their respective cellular environments. Senti Bio's oncology pipeline uses healthy adult donor-derived, natural killer (NK) cells engineered with chimeric antigen receptor (CAR) gene circuits that are cryopreserved and dosed off-the-shelf. Senti Bios oncology pipeline is primarily focused on three preclinical-stage programs: SENTI-202, a Logic Gated (OR+NOT) off-the-shelf CAR-NK cell therapy designed to target and eliminate acute myeloid leukemia (AML) cells while sparing the healthy bone marrow; SENTI-301, a regulatable Multi-Armed off-the-shelf CAR-NK cell therapy designed for the treatment of hepatocellular carcinoma (HCC); and SENTI-401, a Logic Gated (NOT) off-the-shelf CAR-NK cell therapy designed to target and eliminate colorectal cancer (CRC) cells while sparing healthy cells elsewhere in the body. In addition, the company is collaborating with Spark Therapeutics (a member of the Roche Group) and BlueRock Therapeutics (a wholly-owned and independently operated subsidiary of Bayer AG) on applications of its gene circuit technology outside of oncology.

Omid Farokhzad, MD, Executive Chair of the DYNS Board of Directors, said, We believe in the powerful potential of engineering gene circuits with programmable computer-like logic in cell and gene therapies. We look forward to continued progress from the Senti Bio team including advancing product candidates towards and into clinical trials, solidifying its clinical-scale cGMP manufacturing capabilities, and expanding its gene circuit offerings across multiple diseases and modalities via partnering opportunities.

Mostafa Ronaghi, PhD, CEO of DYNS added, We have been very impressed with Sentis approach and platform, which has the potential to define the future of cell and gene therapy. Sentis scientific founders and management are pioneers in the field of mammalian synthetic biology and have assembled a highly qualified team to use this platform to improve the lives of patients in oncology and many other disease categories.

Senti Bio received gross proceeds of approximately $140.3 million of the expected $156.5 million in connection with the business combination, which included funds held in DYNS's trust account of $84.5 million (net of redemptions), $50.6 million of the expected $66.8 million in proceeds from a private investment in public equity (PIPE) financing that closed concurrently with the consummation of the business combination, and a recent $5.2 million investment by Leaps by Bayer, the impact investment arm of Bayer AG, through the purchase of a convertible note that was exchanged (at $10.00 per share, with accrued interest canceled) at the closing of the business combination for common equity with the same rights as the PIPE shares. Senti Bio expects the proceeds from this transaction, combined with cash on hand, to fund operations into 2024.

Investors in DYNS include funds managed by ARK Investment Management LLC, funds and accounts managed by Counterpoint Global (Morgan Stanley Investment Management), Invus, and funds and accounts advised by T. Rowe Price Associates, Inc., among others.

Investors participating in the PIPE financing as of the closing of the business combination included 8VC, Amgen Ventures, funds and accounts managed by Counterpoint Global (Morgan Stanley Investment Management), Invus, NEA, Parker Institute for Cancer Immunotherapy, and T. Rowe Price funds, among others. Of the $66.8 million in subscriptions for the PIPE financing, $16.2 million has yet to be funded as one investor, who entered into a subscription agreement concurrently with Senti Bio and DYNSs execution of the business combination agreement in December 2021, has not funded its commitment. Senti Bio intends to enforce such one investor's legal obligations under its subscription agreement. Solely for purposes of consummating the business combination on June 8, 2022, Senti Bio agreed to waive the $150 million available cash closing condition under the business combination agreement previously entered into with DYNS (as a result of such one investor failing to timely fund its $16.2 million commitment).

DYNSs board members, Dr. Omid Farokhzad and David Epstein, have joined the Senti Bio Board of Directors. The other Senti Bio board members are Susan Berland, Dr. James Collins, Dr. Brenda Cooperstone, Dr. Timothy Lu and Edward Mathers.

Uses of Proceeds and Planned Milestones Proceeds from the transaction are expected to provide Senti Bio with capital to further develop its gene circuit technologies and therapeutic pipeline, including:

Summary of Progress to Date

Advisors J.P. Morgan acted as lead capital markets advisor to DYNS and as co-placement agent to DYNS on the PIPE. Morgan Stanley & Co. LLC acted as financial advisor to DYNS and as co-placement agent to DYNS on the PIPE. BofA Securities acted as exclusive financial advisor to Senti Bio and as co-placement agent to DYNS on the PIPE. Davis Polk & Wardwell LLP acted as legal advisor to DYNS. Goodwin Procter LLP acted as legal advisor to Senti Bio. Latham & Watkins LLP acted as legal advisor to J.P. Morgan, Morgan Stanley & Co. LLC and BofA Securities in their roles as placement agents for the PIPE.

About Senti Bio Our mission is to create a new generation of smarter medicines that outmaneuver complex diseases using novel and unprecedented approaches. To accomplish this, we are building a synthetic biology platform that may enable us to program next-generation cell and gene therapies with what we refer to as Gene Circuits. These Gene Circuits, which are created from novel and proprietary combinations of DNA sequences, are designed to reprogram cells with biological logic to sense inputs, compute decisions and respond to their cellular environments. We aim to design Gene Circuits to improve the intelligence of cell and gene therapies in order to enhance their therapeutic effectiveness, precision and durability against a broad range of diseases that conventional medicines do not readily address. Our synthetic biology platform utilizes off-the-shelf chimeric antigen receptor natural killer (CAR-NK) cells, outfitted with these Gene Circuit technologies, to target particularly challenging liquid and solid tumor oncology indications. Our lead programs include SENTI-202 and SENTI-301. SENTI-202 is a Logic Gated OR+NOT off-the-shelf CAR-NK cell therapy designed to target and eliminate acute myeloid leukemia (AML) cells while sparing the healthy bone marrow. SENTI-301 is a Multi-Armed off-the-shelf CAR-NK cell therapy designed for the treatment of hepatocellular carcinoma (HCC). We anticipate filing Investigational New Drug (IND) applications in 2023 for both candidates. Over the past several months, Senti Bio scientists have presented preclinical proof-of-concept data across various programs including at the annual meetings of the American Society of Gene and Cell Therapy (ASGCT), the American Association for Cancer Research (AACR), and the American Society of Hematology (ASH). We have also demonstrated the breadth of our Gene Circuits in other modalities and diseases outside of oncology and have executed partnerships with Spark Therapeutics and BlueRock Therapeutics to advance these capabilities. For more information, please visit the Senti Bio website at https://www.sentibio.com.

About Dynamics Special Purpose Corp. DYNS was formed in May 2021 for the purpose of effecting a merger, capital stock exchange, asset acquisition, stock purchase, reorganization, or similar business combination with one or more businesses. It focused its search in healthcare and the life sciences, including development platforms that enable applications in prevention, diagnosis, treatment, or advanced biomaterials and, within that context, life-sciences tools, enabling software, synthetic biology and novel drug discovery.

Forward-Looking Statements This press release contains certain forward-looking statements within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995 with respect to DYNS and Senti Bio. These forward-looking statements generally are identified by the words believe, could, predict, continue, ongoing, project, expect, anticipate, estimate, intend, strategy, future, opportunity, plan, may, should, will, would, will be, will continue, will likely result, forecast, seek, target and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. Forward-looking statements are predictions, projections and other statements about future events that are based on current expectations of Senti Bios and DYNSs management and assumptions, whether or not identified in this document, and, as a result, are subject to risks and uncertainties. Forward-looking statements include, but are not limited to, statements regarding estimates and forecasts of financial and performance metrics, projections of market opportunity and market share, expectations and timing related to preclinical, clinical and regulatory milestones, potential benefits of the business combination and the potential success of Senti Bio's business strategy, the initial market capitalization and cash runway of the combined company, the benefits of the business combination, as well as statements about the potential attributes and benefits of Senti Bios product candidates and the progress and timing of Senti Bios product development activities, IND filings and clinical trials and expectations related to the effects of the business combination and the PIPE financing, including the unfunded portion thereof. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by any investor as, a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Senti Bio and DYNS. Many factors could cause actual future events to differ materially from the forward-looking statements in this document, including but not limited to: (i) changes in domestic and foreign business, market, financial, political and legal conditions, (ii) risks that the transaction disrupts current plans and operations of Senti Bio and potential difficulties in Senti Bio employee retention as a result of the transaction, (iii) the outcome of any legal proceedings that may be instituted against Senti Bio or DYNS related to the Business Combination Agreement or the transaction, or any governmental or regulatory proceedings, investigations or inquiries, (iv) volatility in the price of Senti Bios securities, which may arise due to a variety of factors, including changes in the competitive and highly regulated industries in which Senti Bio currently operates and plans to operate, variations in operating performance across competitors, changes in laws and regulations affecting DYNSs or Senti Bios business and changes in the capital structure of the combined company, (v) the ability to implement business plans, forecasts and other expectations after the completion of the transaction, to realize the anticipated benefits of the transaction, and to identify and realize additional opportunities, (vi) the risk of downturns and a changing regulatory landscape in Senti Bios highly competitive industry, (vii) risks relating to the uncertainty of any projected financial information with respect to Senti Bio, (viii) risks related to uncertainty in the timing or results of Senti Bios preclinical studies and any future clinical trials, product acceptance and/or receipt of regulatory approvals for Senti Bios product candidates, (ix) the ability of the combined company to compete effectively and its ability to manage growth, (x) risks related to delays and other impacts from the COVID 19 pandemic, (xi) the ability of the combined company to issue equity or equity-linked securities in the future, and (xii) the success of any future research, development and commercialization efforts by the combined company.

Readers are cautioned not to put undue reliance on forward-looking statements, and Senti Bio assumes no obligation and does not intend to update or revise these forward-looking statements, whether as a result of new information, future events, or otherwise. Senti Bio gives no assurance that Senti Bio will achieve its expectations. The inclusion of any statement in this communication does not constitute an admission by Senti Bio or any other person that the events or circumstances described in such statement are material.

Non-Solicitation This press release does not constitute (i) a solicitation of a proxy, consent or authorization with respect to any securities or in respect of the Business Combination or (ii) an offer to sell, a solicitation of an offer to buy, or a recommendation to purchase any security of Senti Bio, or any of its respective affiliates. No such offering or securities shall be made except by means of a prospectus meeting the requirements of Section 10 of the Securities Act of 1933, as amended.

Additional Information About the Business Combination and Where To Find It DYNS filed a registration statement on Form S-4 (the Registration Statement) with the SEC, which was declared effective on May 13, 2022. The Registration Statement includes a proxy statement/prospectus. The proxy statement/prospectus contains important information about DYNS, Senti Bio and the business combination. Senti Bios stockholders may access a copy of the Registration Statement, as well as other documents filed with the SEC by DYNS, without charge at the SEC's website located at http://www.sec.gov.

INVESTMENT IN ANY SECURITIES DESCRIBED HEREIN HAS NOT BEEN APPROVED OR DISAPPROVED BY THE SEC OR ANY OTHER REGULATORY AUTHORITY NOR HAS ANY AUTHORITY PASSED UPON OR ENDORSED THE MERITS OF THE BUSINESS COMBINATION OR THE ACCURACY OR ADEQUACY OF THE INFORMATION CONTAINED HEREIN. ANY REPRESENTATION TO THE CONTRARY IS A CRIMINAL OFFENSE.

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Senti Bio Debuts as Publicly Traded Company Focused on Developing Next-Generation Cell and Gene Therapies Engineered with Gene Circuits - BioSpace

CMC Joint Arthroplasty at Bone and Joint Institute of Tennessee Successfully Treats Advanced Thumb Joint Arthritis When Other Treatments Fail -…

The development of an opposable thumb in mankind is what has moved us beyond other animals, allowing us to make tools, eat more meat, and evolve a bigger brain. About seven million years ago, we grew a long thumb and shorter fingers allowing us to touch our thumbs to our other fingers. This is why our ancestors were able to throw a spear to kill wild game and hold a writing implement to record our history. However, because we use the thumb joint so much, thumb carpometacarpal (CMC) osteoarthritis is quite common. It affects up to 11% of men and 33% of women in their 50s and 60s. However, in the mid-1980s a successful surgical procedure was developed to return movement to the joint and relieve pain.

Todd Wurth, M.D. performs more than 100 of these surgeries every year, and has been recognized by the Nashville Business Journal many times as one of Nashvilles Best Hand Surgeons. He is a board-certified orthopaedic surgeon specializing in treatment of the shoulder, elbow, hand and wrist. He earned his medical degree in 1998 from the University of Louisville School of Medicine, completed his residency in orthopaedic surgery at the Indiana University Medical Center, then completed fellowship training at Allegheny General Hospital in Pittsburgh in the areas of hand, wrist, elbow, shoulder and microvascular surgery. He is a fellow in the American Academy of Orthopaedic Surgeons and a member of the American Society for Surgery of the Hand with a certificate of added qualifications in surgery of the hand.

Williamson Source: You do a lot of thumb carpometacarpal (CMC) arthroplasties every year. Tell us a little about the surgery?

Dr. Todd Wurth: CMC arthroplasty is a procedure that removes the damaged, arthritic trapezium bone at the base of the thumb and utilizes a tendon that is transferred from the forearm to stabilize the thumb in the absence of the trapezium. This is an exceptionally important joint, one that allows us to have an opposable thumb. The pain and dysfunction resulting from arthritis in the thumb CMC joint can have a huge impact on peoples lives.

There are many ways to complete this operation. A number of companies have developed implants to take the place of the damaged bone, but I prefer the use of my patients own tendon to stabilize the thumb and act as a soft tissue interposition rather than relying on manufactured implants that often only address one side of the arthritic joint and present a whole host of potential complications that are avoidable. I have seen the new technology in this area fail. The original description of this surgery was proposed in 1985 and has undergone some modifications since, but the original premise remains the same and is time tested. I value the idea of surgical procedures that use biologic rather than non-biologic materials to treat a condition when feasible. The biologic options typically outlast those of non-biologics and have lower rates of long-term complications.

After removing the damaged trapezium bone, I transfer a forearm tendon to create a sling that stabilizes the thumb in the absence of the removed trapezium. This transferred tendon actually reconstructs a ligament whose sole purpose is to stabilize the thumb. It is laxity within this original ligament that actually results in the arthritis to begin with. I then use the rest of the tendon to act as a soft tissue interposition to occupy the space of the removed trapezium.

The key to this surgery is stability of the thumb. Some surgeons simply remove the trapezium, which provides relief of the arthritic joint, but fails to stabilize the thumb. Studies have demonstrated similar outcomes to simple bone removal without tendon transfer to those of bone removal with tendon transfer at 1-3 years. Beyond three years, thumbs stabilized with tendon transfer outperformed and outlasted those without tendon transfer. My goal as a surgeon is to provide my patients with the best opportunity for long-lasting success.

WS: What is recovery time? What happens during recovery?

Dr. Wurth: Immediately after surgery the patient is put into a splint that immobilizes the thumb, wrist, and mid-forearm for five days. It is non-removable and must remain dry. After five days, the original splint is removed and replaced with a custom, removable splint that, like the original splint, goes up to the mid-forearm. This is worn day and night for about three weeks, removing it for bathing and wrist range of motion exercises. The fingers are not incorporated and we recommend aggressive finger range of motion from the start. We have patients refrain from heavy lifting and pinching activities, and because of this they may require assistance around the house for a period of time following surgery.

After three weeks in this splint, we cut the splint down to the hand only. This splint only immobilizes the thumb and leaves the wrist free when wearing. This splint is removed several times daily to work on the thumb range of motion including opposing to the other fingers. This splint is worn for approximately two weeks.

Finally, the splint is replaced with a neoprene sleeve. I encourage my patients to refrain from heavy gripping and pinching activities for a period of three months after surgery. At three months, I cut them loose to increase their activities as tolerated and return to all activities. Full return to certain activities can take up to six months.

WS: I know surgery is always a last resort, so what are non-surgical treatments?

Dr. Wurth: There are oral and topical anti-inflammatory medications that help relieve the pain. Over-the-counter versions would be things like Aleve, Motrin, Voltaren Gel or Icy Hot, but there are also prescription strength medications. Splinting is another option which works by adding additional stability to the thumb. Cortisone injections are also an option for temporary relief, but should be used judiciously. More than two a year may actually exacerbate the arthritic process.

WS: Is there any new technology being used to relieve the pain and damage of CMC arthritis?

Dr. Wurth: Work is being done on stem cell injections, but I would suggest holding off on this treatment until more research has been implemented. True stem cell lines are currently limited to research facilities. Facilities offering stem cell treatment in the community typically lack the quality and quantity of stem cell lineage to offer meaningful results. I have expectations that someday we may be able to use stem cell treatment to regenerate cartilage, but we are not there yet.

WS: As we age, we all get aches and pains? When will a patient know it is time to see you about the pain in their thumb?

Dr. Wurth: My recommendation to patients has always been that when their ailments, in this case basilar thumb pain, begin to affect what they need to do or what they want to do on a daily basis, then its time to come see me to discuss options for alleviating their symptoms.

If a patient has had a previous CMC surgery that is no longer relieving their pain, like those done with implants, they can be re-evaluated for revision surgery.

WS: Can anything be done to prevent thumb arthritis?

Dr. Wurth: Thumb arthritis is typically caused by a lack of stability in the CMC joint. Genetics plays a big role and women are more prone to it than men by a ratio of 7:1.

While some jobs are harder on the thumb joint than others, supporting the joint with a splint and changing thumb usage to minimize the strain that exacerbates laxity are ways to lessen the chance of developing arthritis or slowing its progress.

If you are suffering from arthritic pain and want more information, contact Dr. Wurth at Bone and Joint Institute of Tennessee.

To learn more about dealing with CMC arthritis joint pain, contact Dr. Wurths office at (615) 791-2630. Or schedule an appointment online.

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CMC Joint Arthroplasty at Bone and Joint Institute of Tennessee Successfully Treats Advanced Thumb Joint Arthritis When Other Treatments Fail -...